An international collaborative study led by Australian scientists at the University of Queensland in Brisbane has demonstrated that dietary selenium supplementation mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging in mice.

Notably, selenium supplementation was demonstrated to restore neurogenesis and reverse cognitive decline in aging and in a mouse model of hippocampal injury, suggesting potential therapeutic relevance.

"This is the first study to show that selenium supplementation mediates exercise-induced adult neurogenesis and reverses injury- and aging-induced learning deficits in vivo," said lead researcher Tara Walker, a research fellow in the Queensland Brain Institute at The University of Queensland.

Reported in the February 3, 2022, edition of Cell Metabolism, the study was co-led by Gerd Kempermann, a professor in the Center for Regenerative Therapies at the Technical University of Dresden, Germany, and Sheng-Tao Hou, professor and director of the Brain Research Centre at Southern University of Science and Technology in Shenzhen, China.

Adult hippocampal neurogenesis provides structural plasticity to the brain, allowing life-long flexibility supporting effective learning and memory, with this process being thought to underlie critical cognitive processes in humans.

The two major adult neural stem cell niches in the hippocampal dentate gyrus and the lateral ventricle subventricular zone share many common features, but are under distinct systemic regulatory control.

A key difference between the neural precursor cells (NPCs) of these neurogenic niches concerns their susceptibility to proliferation in response to physiological stimuli, said Walker. "While NPCs can be stimulated by various physiological stimuli, including environmental enrichment, probably the most widely-studied such stimulus is physical exercise."

Physical exercise

The broad range of effects physical exercise on the body suggests the involvement of systemic mediators of neurogenesis facilitating the direct access of systemic blood-borne factors exclusively into hippocampal NPCs.

A previous proteomic screening study of blood plasma from mice housed in either standard cages or in those with a running wheel for four days investigated systemic mechanisms whereby exercise regulates hippocampal neurogenesis.

Among proteins identified with significantly increased running-induced plasma levels, those of the antioxidant selenium transporter selenoprotein P (SEPP1) were approximately double in running mice versus controls.

Among the 25 mammalian selenoproteins identified, SEPP1 is the most important for maintaining brain selenium levels via its receptor, low-density lipoprotein preceptor-related protein 8 (LRP8), at the blood-brain barrier (BBB).

"SEPP1 transports the most selenium in the blood and is responsible for transporting selenium across the BBB via the receptor LRP8," Walker told BioWorld Science.

Moreover, the aforementioned activity-dependent increase in blood SEPP1 levels suggests a potential role for selenium in activation of quiescent NPCs.

In the new Cell Metabolism study, the authors investigated whether a SEPP1-mediated increase in selenium transport underlies the exercise-induced increase in adult hippocampal neurogenesis.

They also determined whether mimicking the effect of exercise by dietary selenium supplementation could restore neurogenesis and reverse cognitive decline associated with aging and hippocampal injury.

Using genetic knock out (KO) mouse models, they confirmed that SEPP1 and its receptor LRP8 were required for the exercise-induced increase in adult hippocampal neurogenesis.

"The exercise-induced increase in hippocampal NPC proliferation that would normally be seen in wild-type mice was no longer observed in Sepp1 and Lrp8 KO mice, indicating that selenium transport may be involved in mediating this effect," said Walker.

In addition, the researchers demonstrated that in vivo selenium infusion significantly increased hippocampal NPC proliferation and adult neurogenesis.

The extent of these increases "varied according to the age of the mice and the delivery method used i.e. brain infusion versus dietary supplementation," noted Walker.

However, "in young mice in which selenium was infused directly into the hippocampus, we observed a more than four-fold increase in NPC proliferation," she told BioWorld Science.

Importantly, mimicking the effect of exercise through dietary selenium supplementation was shown to restore neurogenesis and reverse the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance.

"Given that selenium is a natural dietary compound, it could readily be incorporated into the diets of elderly individuals or those that have had a stroke," said Walker.

These study findings collectively provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent neurogenic recruitment.

Looking ahead, "we will continue to work with our collaborators to study the potential benefits of selenium in other neurological conditions, including cerebral ischemia," said study co-leader Hou.

"We are also investigating selenium supplementation in other neurodegenerative conditions and studying the underlying mechanisms whereby selenium exerts this neuroprotective function," said Walker.

"We are particularly interested in selenium supplementation in the more canonical stroke model of middle cerebral artery occlusion, which more closely resembles the human stroke condition."